California Institute Research Articles

Hippo Signaling Pathway has a critical role in Zika Virus Replication and in the Pathogenesis of Neuroinflammation

Zika virus (ZIKV) is a reemerging human pathogen that causes congenital abnormalities including microcephaly and eye disease. The cell/molecular basis of ZIKV and host interactions inducing ocular and neuronal pathogenesis are unclear. Here we noted that the Hippo/SWH signaling pathway, which controls organ size through progenitor cell proliferation and differentiation, is dysregulated following ZIKV infection. In human fetal retinal pigment epithelial (RPE) cells, there is an early induction of transcriptional co‐activator, YAP, which is later degraded with a corresponding activation of the TBK1‐IRF3 Type I interferon pathway. YAP/TAZ silencing results in reduced ZIKV replication, indicating a direct role of Hippo pathway in regulating ZIKV infection. Using an in vivo Ifnr1−/− knockout mice model, ZIKV infection was found to reduce YAP/TAZ protein levels while increasing pYAP Ser127 in the retina and brain. Hippo pathway is activated in major components of the blood‐brain barrier (BBB), incuding endothelial cells and astrocytes. In addition, our data shows AMPK signaling pathway’s role in regulating YAP/TAZ in ZIKV‐infected cells. Our data demonstrates ZIKV infection initiates a crosstalk among AMPK‐Hippo‐TBK1 pathways, which regulate antiviral and energy stress responses during oculo‐neuronal inflammation.Support or Funding InformationThis work was funded by California Institute for Regenerative Medicine (CIRM) Quest – Discovery Stage Research Projects Grant (DISC2‐10188) to V.A. at the University of California, Los Angeles.

Contraceptive Attitudes and beliefs Among Hmong Young Adults

Introduction: While different contraceptive attitudes have been reported among different ethnic groups inthe US, little if any research has been conducted to understand the reproductive health needs and attitudesamong Hmong young adults. To our knowledge, this is the first study to investigate the relationship amongcontraceptive perception of this community. Objective: The purpose of this research was to identify attitudesthat influence Hmong college students’ contraceptive practices. Methods: A campus-wide online survey wasused as part of the data collection at a midsize institution in Central California. The questionnaire was a 32-items scale instrument called Contraceptive Attitude Scale (CAS), developed by Dr. Black. Results: Three hundred and forty-four students successfully completed the 32-items scale instrument CAS, which measured general contraceptive attitudes among Hmong young adults in rural California. The data reveals a high prevalence of unmarried (85%) Hmong college students reporting being sexually active (67%), with 62% having at least one sexual partner over the past 12 months; however, only 36% reported to use condom compared to 58% who did not use condoms during the last time of sexual intercourse. Conclusion: The findings indicated statistically significant differences between groups on the characteristics of sexual partners, contraceptive methods, marital status, birthplace, primary language spoken at home, years spent in college and years lived in the United States. The findings greatly contribute to the understanding of factors that influence contraceptive choices among the Hmong college population. More importantly, the information is crucial in designing programs to promote contraceptive knowledge and practices that are specific to the Hmong.

Sustainability, collaboration, and innovation

Sustainability seems to have a lot of momentum these days, and that is good for the future of chemistry and our society. In the past 2 years, C&EN reported on the following news: The US House of Representatives passed a sustainable chemistry bill. The California Institute of Technology received a $750 million gift for sustainability research from Stewart and Lynda Resnick. Mitsubishi Chemical Holdings opened a sustainability center at Arizona State University. Sustainable Bioproducts invested $33 million to develop edible proteins. Procter & Gamble unveiled sustainability goals, including making the packaging of its top 20 brands 100% recyclable or reusable. Sustainability is needed to preserve the quality of life on this planet, and it represents an investment in our children and their future. The practice of sustainability can decrease energy use, reduce waste, minimize the use of materials, and reduce hazards and risks. The mission of the American Chemical Society

Steering selective stereochemistry from racemic alkyls

Making carbon-carbon bonds is hard. Linking racemic mixtures of two alkyls while simultaneously controlling the stereochemistry of both ends of the product is nigh impossible. Gregory Fu, together with his colleagues at the California Institute of Technology, has found a way to make it easy. Using a chiral nickel catalyst, Fu coupled a racemic mixture of electrophiles and nucleophiles with up to 82% yield and 95% stereoselectivity (Science 2020, DOI: 10.1126/science.aaz3855). What’s more, this unlikely reaction is compatible with 19 functional groups. Most substitution reactions for forming the C–C bonds critical to pharmaceutical manufacturing have major limitations. They work for only some alkyl compounds and often lead to side reactions, especially with bulky substituents. Plus, these reactions tend to form a racemic mixture of products. But usually only one isomer of a pharmaceutical compound is biologically active. For the catalyst to be stereoselective, its ligand needs to discern between the

A phase Ib/II study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients.

114 Background: Magrolimab (M, Hu5F9-G4) is an antibody targeting CD47, a macrophage “don’t eat me” signal that demonstrates preclinical synergy with cetuximab (C) in refractory KRAS wild type (KRASwt) and KRAS mutant (KRASm) colorectal (CRC) tumors. Methods: Phase (Ph) 1 doses of M+C were escalated in solid tumor patients (pts) and Ph 2 efficacy was explored in previously treated KRASwt and KRASm CRC patients. Day 1 priming with 1 mg/kg of M was used to mitigate on-target anemia followed by maintenance doses ranging from 10 to 45 mg/kg in combination with C. Ph 2 pts were treated with 30 or 45 mg/kg of M and 400/250 mg/m2 of C. Results: In 78 treated pts (32 Ph 1 and 46 Ph 2), the median age was 59 years (range 19-82), and median prior therapies was 5 (range 1-14). No maximum tolerated dose was reached. Treatment-related adverse events (TRAEs) of any Grade (G) included dermatitis acneiform 36%, dry skin 33%, fatigue 32%, infusion reactions 31%, headache 30%, diarrhea 23%, nausea 23%, chills 23%, and anemia 22%. There were no fatal TRAEs and 3/78 (4%) discontinued M treatment due to any adverse events. In the combined Ph 1+2 study, 2 of 30 evaluable KRASwt CRC pts had confirmed PRs for 7.0 and 12.5 months (mo), for a 6.7% objective response rate (ORR). Both had prior C treatment. The median progression-free survival (mPFS) and median overall survival (mOS) was 3.6 mo (95%CI 1.8-5.4) and 10.1 mo (95%CI: 6.9-14.4), respectively. In 40 evaluable KRASm pts, there were no responses but 45% had stable disease (SD) and the mPFS and mOS were 1.9 mo (95%CI: 1.8-3.5) and 10.4 mo (95%CI: 5.7-16.4), respectively. In 28 KRASm pts who were TAS102/regorafenib naïve, preliminary mOS was 12.4 mo (95%CI: 5.9-not reached) which is longer than that reported for historical controls. Tumor biopsies showed treatment-related increases in macrophage immune cell infiltrates in SD pts, and baseline T cell infiltration was associated with longer OS. Pharmacokinetic profiles will be presented. Conclusions: M+C is a novel, well-tolerated combination immunotherapeutic treatment regimen. Responses were observed in two previously treated CRC pts and survival is encouraging in KRASm pts. Funded by Forty Seven and California Institute for Regenerative Medicine. Clinical trial information: NCT02953782.

Machiite, Al2Ti3O9, a new oxide mineral from the Murchison carbonaceous chondrite: A new ultra-refractory phase from the solar nebula

Abstract Machiite (IMA 2016-067), Al2Ti3O9, is a new mineral that occurs as a single euhedral crystal, 4.4 μm in size, in contact with an euhedral corundum grain, 12 μm in size, in a matrix of the Murchison CM2 carbonaceous chondrite. The mean chemical composition of holotype machiite by electron probe microanalysis is (wt%) TiO2 59.75, Al2O3 15.97, Sc2O3 10.29, ZrO2 9.18, Y2O3 2.86, FeO 1.09, CaO 0.44, SiO2 0.20, MgO 0.10, total 99.87, giving rise to an empirical formula (based on 9 oxygen atoms pfu) of (Al1.17Sc0.56Y0.10Ti0.084+Fe0.06Ca0.03Mg0.01)(Ti2.714+Zr0.28Si0.01)O9. The general formula is (Al,Sc)2(Ti4+,Zr)3O9. The end-member formula is Al2Ti3O9. Machiite has the C2/c schreyerite-type structure with a = 17.10 Å, b = 5.03 Å, c = 7.06 Å, β = 107°, V = 581 Å3, and Z = 4, as revealed by electron backscatter diffraction. The calculated density using the measured composition is 4.27 g/cm3. The machiite crystal is highly 16O-depleted relative to the coexisting corundum grain (Δ17O = –0.2 ± 2.4‰ and –24.1 ± 2.6‰, respectively; where Δ17O = δ17O – 0.52 × δ18O). Machiite is a new member of the schreyerite (V2Ti3O9) group and a new Sc,Zr-rich ultrarefractory phase formed in the solar nebula, either by gas-solid condensation or as a result of crystallization from a Ca,Al-rich melt having solar-like oxygen isotopic composition (Δ17O~ –25‰) under high-temperature (~1400–1500 °C) and low-pressure (~10-4–10-5 bar) conditions in the CAI-forming region near the protosun. The currently observed disequilibrium oxygen isotopic composition between machiite and corundum may indicate that machiite subsequently experienced oxygen isotopic exchange with a planetary-like 16O-poor gaseous reservoir either in the solar nebula or on the CM chondrite parent body. The name machiite is in honor of Chi Ma, mineralogist at California Institute of Technology, for his contributions to meteorite mineralogy and discovery of many new minerals representing extreme conditions of formation.

Commemorating Frances Arnold

Frances H. Arnold is the Linus Pauling Professor of Chemical Engineering, Bioengineering, and Biochemistry at the California Institute of Technology, and Director of Caltech’s Rosen Bioengineering Center. Anyone reading this Retrospective probably knows that Frances was awarded the Nobel Prize in Chemistry in 2018 for the directed evolution of enzymes. She is also only the fifth woman to ever win this prize, and the First American woman to win it. The list of Frances’ prior honors and awards is extensive and astounding, and includes elections to the National Academy of Engineering (2000), the National Academy of Medicine (2004), and the National Academy of Sciences (2008) (the first woman to be elected to all three), the 2011 NAE Draper Prize (the first woman to receive it), and the 2016 Millennium Technology Prize (first woman to win). At the time of this writing, Google Scholar reports her co-authored publications receiving over 50,000 citations, with an h-index of 122. She is co-founder of Gevo, Inc. (producing carbon-neutral biofuels) and Provivi (producing environmentally safe biopesticides), and was recently appointed to the board of directors for Alphabet, Inc. (the parent company of Google).

Optimization Algorithms for Large-Scale Systems

Brief Biography: Navid Azizan is a fifth-year PhD candidate in Computing and Mathematical Sciences (CMS) at the California Institute of Technology (Caltech), where he is co-advised by Adam Wierman and Babak Hassibi, and is a member of multiple research groups: DOLCIT, RSRG and SISL. During the summer of 2019, he was a research scientist intern at Google DeepMind. He received the B.Sc. degree in EE form Sharif University of Technology and the M.Sc. degree in ECE from the University of Southern California, in 2013 and 2015, respectively. His research interests broadly lie in mathematical optimization, machine learning, networks, and markets. He is the recipient of several awards, including the 2016 ACM GreenMetrics Best Student Paper Award, the Amazon Fellowship in Artificial Intelligence, the PIMCO Fellowship in Data Science, the Caltech CMS Fellowship, and the USC Provost's Fellowship.

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies.

Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life‐threatening complications from transplant. This Perspective serves to highlight these needs through examples from the recent CIRM‐funded and other notable investigations, presents rationale for comprehensive, systematic, and focused strategies to unleash the full potential of HSCT, thereby enabling cures for a greatly expanded number of disorders and making HSCT feasible, accessible, and affordable to all who could benefit.

A Statistical Method for Associating Earthquakes with Their Source Faults in Southern California

ABSTRACT We present a new statistical method for associating earthquakes with their source faults in the Southern California Earthquake Center’s 3D Community Fault Models (CFMs; Plesch et al., 2007) in near-real time and for historical earthquakes. The method uses the hypocenter location, focal mechanism orientation, and earthquake sequencing to produce the probabilities of association between a given earthquake and each fault in the CFM as well as the probability that the event occurred on a fault not represented in the CFM. We used a set of known likely associations (the Known Likely Sets) as training or testing data and demonstrated that our models perform effectively on these examples and should be expected to perform well on other earthquakes with similar characteristics including the full catalog of southern California earthquakes (Hauksson et al., 2012). To produce near-real-time associations for future earthquakes, the models have been implemented as an R script and connected to the Southern California Seismic Network data processing system operated by the California Institute of Technology and the U.S. Geological Survey to automatically produce fault associations for earthquakes of M≥3.0 as they occur. To produce historical associations, we apply the method to the most recent CFM version (v.5.2), yielding modeled historical associations for all events of M≥3.0 in the catalog of southern California earthquakes from 1981 to 2016. More than 80% of these events and 99% of moment within the geography covered by the CFM had a primary association with a CFM fault. The models can help identify clusters of small earthquakes that indicate the onset of activity associated with major faults. The method will also assist in communicating objective information about the faults that source earthquakes to the scientific community and general public. In the event of a damaging southern California earthquake, the near-real-time association will provide valuable information regarding the similarity of the current event to forecast scenarios, potentially aiding in earthquake response.

Commentary on the Recruitment and Retention of American Indian and Alaska Native Students in California Postsecondary Education Institutions

In this commentary, we engage and summarize existing practices for recruiting and retaining American Indian and Alaska Native students in postsecondary institutions in California. This commentary is the output of a two-day symposium, “Lighting a Path Forward: UC Land Grants, Public Memory, and Tovaangar,” held at the University of California, Los Angeles in October of 2019. The symposium brought together campus and community leaders from across California to discuss the past, present and future of American Indian and Alaska Native student and community concerns, and provide intervening policy and practice recommendations. Participants included both American Indian and Alaska Native and non-Native individuals with a wealth of professional experience and employment in American Indian and Alaska Native education, from the California Community College, California State University and University of California systems. We jointly created a table of critical interventions in education, the justification for this, and potential strategies for implementation. Here, we summarize the discussion of participants from the American Indian and Alaska Native student retention and recruitment workshop to document recommends interventions for campus practitioners and leaders to serve as a guiding document for system and campus advocacy.

Opportunities and challenges in commercial pharmaceutical liposome applications.

In the 1980s, the center of entrepreneurial activity for the application of liposome science to medicine took the form of a company called Vestar Inc. (which became NeXstar Pharmaceuticals Inc., and eventually a division of Gilead Sciences, with merger and acquisition activity). This company was formed from science initially developed at the California Institute of Technology and the City of Hope, and involving several other local academic and treatment centers. This company eventually produced two commercial liposomal therapeutics, and created a particular paradigm of formulation goals, formulation development, characterization, and production unique among the set of companies that emerged around the same time. A number of clinical candidates were also developed, but failed to achieve commercialization. Nevertheless, several of these provide still relevant lessons and guidance for the field. Key adaptations of this technology to lower cost applications have also been carried out and are examined.

Machiite, Al2Ti3O9, a new oxide mineral from the Murchison carbonaceous chondrite: A new ultrarefractory phase from the solar nebula

Machiite (IMA 2016-067), Al 2 Ti 3 O 9 , is a new mineral that occurs as a single euhedral crystal, 4.4 μm in size, in contact with an euhedral corundum grain, 12 μm in size, in a matrix of the Murchison CM2 carbonaceous chondrite. The mean chemical composition of holotype machiite by electron probe microanalysis is (wt%) TiO 2 59.75, Al 2 O 3 15.97, Sc 2 O 3 10.29, ZrO 2 9.18, Y 2 O 3 2.86, FeO 1.09, CaO 0.44, SiO 2 0.20, MgO 0.10, total 99.87, giving rise to an empirical formula (based on 9 oxygen atoms pfu) of (Al1.17Sc0.56Y0.10Ti0.084+Fe0.06Ca0.03Mg0.01)(Ti2.714+Zr0.28Si0.01)O9.$\left( \text{A}{{\text{l}}_{1.17}}\text{S}{{\text{c}}_{0.56}}{{\text{Y}}_{0.10}}\text{Ti}_{0.08}^{4+}\text{F}{{\text{e}}_{0.06}}\text{C}{{\text{a}}_{0.03}}\text{M}{{\text{g}}_{0.01}} \right)\left( \text{Ti}_{2.71}^{4+}\text{Z}{{\text{r}}_{0.28}}\text{S}{{\text{i}}_{0.01}} \right){{\text{O}}_{9}}.$The general formula is (Al,Sc) 2 (Ti 4+ ,Zr) 3 O 9 . The end-member formula is Al 2 Ti 3 O 9 . Machiite has the C 2 /c schreyerite-type structure with a = 17.10 Å, b = 5.03 Å, c = 7.06 Å, b = 107°, V = 581 Å 3 , and Z = 4, as revealed by electron backscatter diffraction. The calculated density using the measured composition is 4.27 g/cm 3 . The machiite crystal is highly 16 O-depleted relative to the coexisting corundum grain (ᐃ 17 O = –0.2 ± 2.4‰ and –24.1 ± 2.6‰, respectively; where ᐃ 17 O = δ 17 O– 0.52 × δ 18 O). Machiite is a new member of the schreyerite (V 2 Ti 3 O 9 ) group and a new Sc,Zr-rich ultrarefractory phase formed in the solar nebula, either by gas-solid condensation or as a result of crystallization from a Ca,Al-rich melt having solar-like oxygen isotopic composition (ᐃ 17 O ~ –25‰) under high-temperature (~1400–1500 °C) and low-pressure (~10 -4 –10 -5 bar) conditions in the CAI-forming region near the protosun. The currently observed disequilibrium oxygen isotopic composition between machiite and corundum may indicate that machiite subsequently experienced oxygen isotopic exchange with a planetary-like 16 O-poor gaseous reservoir either in the solar nebula or on the CM chondrite parent body. The name machiite is in honor of Chi Ma, mineralogist at California Institute of Technology, for his contributions to meteorite mineralogy and discovery of many new minerals representing extreme conditions of formation.

Our Inaugural Early Career Advisory Board

Our Inaugural Early Career Advisory Board

Failure to launch: Obstacles to developing a graduate executive leadership degree in a competency‐based education format

AbstractCompetency‐based education (CBE) is an approach that evaluates the mastery of learning from a performance basis, rather than a seat‐time basis. A CBE learner can capitalize on his or her experience from educational settings, work environments, or avocational background to demonstrate proficiency through prescribed academic and industrial outcomes. Utilizing a case study approach, this paper explores the obstacles to implement a graduate executive leadership CBE program at a faith‐based, adult‐learner institution in California. Budget implications, psychometric structures, assessment protocols, and competency identification are evaluated and described. In particular, this disruptive innovation highlights the topics of senior‐level support, infrastructural investment, and faculty and staff involvement.

With the wizard of the unit circle—An appreciation of T. Y. Wu

An account of my interactions with Prof. Theodore Yao-tsu Wu of the California Institute of Technology.

Making ethylene from air and electrons

In the hopes of slowing climate change, researchers are seeking ways to get rid of planet-warming carbon dioxide. Making something valuable from it in the process, such as commodity chemicals, is a double win. Researchers at the University of Toronto and the California Institute of Technology now report they have carried off such a trick by improving the efficiency of a process to make the plastics precursor ethylene from CO2 electrochemically (Nature 2019, DOI: 10.1038/s41586-019-1782-2). There’s a huge existing market for ethylene, says Edward Sargent, an electrical engineer at the University of Toronto. But the compound also has a big CO2 footprint because its manufacture is fossil fuel based. “So if we could instead make renewable ethylene,” Sargent says, “we could displace some of the use of fossil fuel–derived ethylene, and we could consume rather than emit CO2 while we’re doing it.” For this work, Sargent and coworkers teamed up

Інституційні та професійні цінності академічного персоналу університетів США

The problem of value priorities in the US universities is actualized in the paper; they traditionally show high ranking positions and make the majority among the best higher education institutions in the international education and research areas. The fundamental institutional values of the Massachusetts Institute of Technology, Stanford University, California Institute of Technology, Harvard University and University of Wisconsin-Whitewater are revealed aimed at implementing the best American universities experience for the development of higher education system and its quality in Ukraine. It is proven that American universities function on the basis of their own academic values and have their own culture and philosophy in addition to the established institutional values, such as institutional autonomy, academic freedom and shared governance. Consolidating the mission, vision and priorities of higher education institution development the institutional values reflect the peculiarities of the university’s activities and project the moral ideal of behavior of academic staff, students and graduates, who confirm to stakeholders their competitiveness at the labor market. It is revealed that a key and integral part of professional values in the US universities is academic freedom though which historically and traditionally the defense of democratic values is considered. It is grounded that academic freedom in the American university society is a prerequisite for developing knowledge, conducting research and publishing their results, it also causes the social and institutional responsibility, in particular for compliance with ethical standards of conduct and principles of integrity. It is reveled that the practical realization of the American professor’s right for academic freedom is the right for tenured appointment, which makes it possible to work without the administrative pressure and the risk to be fired because of his unpopular views and statements. It is established that the American Association of University Professors is the founder of the American understanding of academic freedom and the advocate of the universities’ academic staff rights, including their tenure.

Open-Source ANSS Quake Monitoring System Software

AbstractANSS stands for the Advanced National Seismic System of the U.S.A., and ANSS Quake Monitoring System (AQMS) is the earthquake management system (EMS) that most of its member regional seismic networks (RSNs) use. AQMS is based on Earthworm, but instead of storing files on disk, it uses a relational database with replication capability to store pick, amplitude, waveform, and event parameters. The replicated database and other features of AQMS make it a fully redundant system. A graphical user interface written in Java, Jiggle, is used to review automatically generated picks and event solutions, relocate events, and recalculate magnitudes. Add-on mechanisms to produce various postearthquake products such as ShakeMaps and focal mechanisms are available as well. It provides a configurable automatic alarming and notification system. The Pacific Northwest Seismic Network, one of the Tier 1 ANSS RSNs, has modified AQMS to be compatible with a freely available, capable, open-source database system, PostgreSQL, and is running this version successfully in production. The AQMS Software Working Group has moved the software from a subversion repository server hosted at the California Institute of Technology to a public repository at gitlab.com. The drawback of AQMS as a whole is that it is complex to fully configure and comprehend. Nevertheless, the fact that it is very capable, documented, and now free to use, might make it an attractive EMS choice for many seismic networks.

Radiation-resistant solar cells for space

Solar cells made with nanowires can tolerate up to 40 times as much high-energy radiation as those made of flat crystalline films, making the nano versions well suited for powering satellites and spacecraft (ACS Nano 2019, DOI: 10.1021/acsnano.9b05213). Harry A. Atwater of the California Institute of Technology and colleagues fabricated solar cells with a light-absorbing layer made of an array of either 3 µm long gallium arsenide or 2 µm long indium phosphide nanowires grown vertically from the substrate. The researchers irradiated the devices with protons at 100 and 350 keV, comparable to what they would experience in space. Compared with thin-film solar cells made from the same materials, the nanowire solar cells withstood 10–40 times as many protons before their current degraded. Simulations showed that energetic protons shoot out of nanowires, minimizing damage, while they lodge in crystalline films. The researchers think that the higher surface area of the